Embryonic exposure to acetyl-L-carnitine protects against valproic acid-induced cardiac malformation in zebrafish model

Worldwide, estimated counts of about 7.9 million children are born with serious birth defects. In addition to genetic factors, prenatal exposure to drugs and environmental toxicants represents a major contributing factor to congenital malformations. In earlier investigation, we explored cardiac malformation caused by valproic acid (VPA) during early developing stages of zebrafish. Since heart depends on mitochondrial fatty acid oxidative metabolism for energy demands in which carnitine shuttle has a major role, the present study aimed to investigate the effect of acetyl-L-carnitine (AC) against VPA-induced cardiac malformation in developing zebrafish. Initially, AC was subjected to toxicological evaluation, and two micromolar concentrations (25 mu M and 50 mu M) were selected for evaluation. A sub-lethal concentration of VPA (50 mu M) was selected to induce cardiac malformation. The embryos were grouped and the drug exposures were made at 2.5 h post-fertilization (hpf). The cardiac development and functioning was monitored. A progressive decline in cardiac functioning was noted in group exposed to VPA 50 mu M. At 96 hpf and 120 hpf, the morphology of heart was severely affected with the chambers which became elongated and string-like accompanied by histological changes. Acridine orange staining showed accumulation of apoptotic cells. Group exposed to VPA 50 mu M with AC 50 mu M showed a significant reduction in pericardial sac edema with morphological, functional and histological recovery in developing heart. Moreover, reduced number of apoptotic cells was noted. The improvement with AC might be due to restoration of carnitine homeostasis for cardiac energy metabolism in developing heart.

Automated summary

Approximately 7.9 million children worldwide are born with serious birth defects, and prenatal exposure to drugs and environmental toxicants plays a significant role in these malformations. This study focused on investigating the effect of acetyl-L-carnitine (AC) in mitigating cardiac malformation caused by valproic acid (VPA) in developing zebrafish. The results showed that AC significantly reduced the severity of VPA-induced cardiac malformation.